Visible light photocatalysis of radical anion hetero-Diels-Alder cycloadditions

Article abstract of DOI:10.1016/j.tet.2011.02.066

We have discovered a photocatalytic intramolecular hetero-Diels-Alder reaction of tethered bis(enones). This transformation involves the intermediacy of an enone radical anion and constitutes the formal coupling of an electron-deficient heterodiene with a

Full text of DOI:10.1016/j.tet.2011.02.066

Tetrahedron 67 (2011) 4442e4448
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Visible light photocatalysis of radical anion hetero-DielseAlder cycloadditions
*
Anna E. Hurtley, Megan A. Cismesia, Michael A. Ischay, Tehshik P. Yoon
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have discovered a photocatalytic intramolecular hetero-DielseAlder reaction of tethered bis(enones).
This transformation involves the intermediacy of an enone radical anion and constitutes the formal
coupling of an electron-deficient heterodiene with an electronically mismatched enone dienophile. The
diastereoselectivity and regioselectivity of the process are high, and the dihydropyran products are
amenable to a variety of synthetically useful transformations.
Received 13 January 2011
Received in revised form 17 February 2011
Accepted 22 February 2011
Available online 1 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Hetero-DielseAlder cycloaddition
Photocatalysis
Radical anion
1. Introduction
explore the chemistry of these reactive intermediates, whose utility
in synthesis has been underdeveloped in comparison to that of
Tetrahydropyrans and related six-membered heterocycles are
ubiquitous substructures found in a variety of carbohydrates, pol-
yketide natural products, and other bioactive compounds. Among
the most powerful methods for the rapid construction of densely
functionalized six-membered oxaheterocycles are formal hetero-
DielseAlder cycloadditions. These methods have been the subject of
numerous reviews1 and have been extensively utilized as key steps
in the synthesis of many complex organic structures.2 Nevertheless,
hetero-DielseAlder cycloadditions proceed efficiently under mild
conditions only when the components are electronically well
matched, which involves the reaction of either electron-rich dienes
with electron-deficient carbonyl compounds or electron-poor het-
erodienes with electron-rich olefins. Electronically mismatched
hetero-DielseAlder cycloadditions between two electron-deficient
components typically require forcing conditions that limit their
utility in synthesis.3
neutral radicals. In this paper, we report that high-yielding and
highly diastereoselective radical anion hetero-DielseAlder cyclo-
additions between electronically mismatched enones can be con-
ducted using our group’s strategy for visible light photocatalysis.
2. Results and discussions
Our interest in the hetero-DielseAlder cycloaddition began
during an exploration of the scope of the photocatalytic intra-
molecular [2þ2] enone cycloaddition developed in our labs. We
observed that the length of the aliphatic tethering group had
a dramatic influence on the intrinsic reactivity of the system
(Scheme 1). Bis(enone) 1 bearing a three-carbon tether undergoes
efficient [2þ2] cycloaddition upon irradiation with visible light in
the presence of RuðbpyÞ32þ with LiBF4 and i-Pr2NEt as additives.4a
However, when bis(enone) 3, in which the tether length was in-
creased by one methylene unit, was subjected to the same condi-
tions, the expected [2þ2] cycloadduct was not formed. Instead, the
major products are the hetero-DielseAlder cycloadduct 4 and the
product of reductive monocyclization (5). Both products are formed
with high diastereoselectivity. While analogous compounds were
reported to be side products in the electrochemically induced [2þ2]
cycloadditions of 1 reported by Bauld and Krische,7 we did not
observe their formation in our studies of the photocatalytic cyclo-
addition of 1. Intrigued by this unexpected reactivity, we elected to
initiate an examination of this hetero-DielseAlder process by de-
veloping conditions that allow selective access to [4þ2] cyclo-
adduct 4.
We,4 along with several other research groups,5 have recently
begun to explore the ability of metal polypyridyl photocatalysts to
promote a variety of synthetically useful transformations upon ir-
radiation with visible light.6 In particular, our lab has become in-
terested in exploiting the ability of RuðbpyÞ23þ and related
photoredox catalysts to initiate one-electron transfer processes
without the need for strong stoichiometric reductants or oxidants.
The facility with which radical cations and radical anions can be
generated under photocatalytic conditions has enabled us to
* Corresponding author. E-mail address: tyoon@chem.wisc.edu (T.P. Yoon).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.066

A.E. Hurtley et al. / Tetrahedron 67 (2011) 4442e4448
4443
is crucial for successful cycloaddition,9 as it is in the analogous [2þ2]
cycloaddition reactions reported by our group.4a
O
O
5 mol% Ru(bpy)3Cl2
i-Pr2NEt, LiBF4
COPh
COPh
Ph
Ph
2
89% yield
>10:1 d.r.
We next conducted a survey of the scope of the hetero-
DielseAlder cycloaddition, and the results are summarized in Table
2. A number of symmetrical aryl bis(enones) were found to be
excellent substrates for this reaction. Both electron-deficient (en-
tries 2e3) and electron-rich (entry 4) aryl enones react in high yield
and diastereoselectivity, as do polyaromatic (entry 5) and hetero-
aryl enones (entry 6). Fluoride substitution at the ortho position is
well tolerated (entry 7), although larger groups at this position
significantly hinder reactivity (entry 8). In all cases, the desired
[4þ2] cycloadduct was formed with excellent diastereoselectivity.
H
H
visible light
MeCN
50 min
1
O
H
O
O
Ph
O
Ph
5 mol% Ru(bpy)3Cl2
i-Pr2NEt, LiBF4
Ph
Ph
COPh
COPh
visible light
MeCN
9.5 h
H
4, 46%
>10:1 d.r.
5, 28% yield
>10:1 d.r.
3
visible light,
Ru(bpy)3Cl2
Table 2
Scope of the photocatalytic [4þ2] cycloadditiona
i-Pr2NEt, LiBF4
24 h
Entry
Methodb
Substrate
Product
Time
Yield %c
(33%)
Scheme 1. Photocatalytic [2þ2] and [4þ2] cycloadditions.
We noted that under our initial conditions the selectivity for
formation of 4 over the undesired reductive cyclization product 5
was high at relatively low conversions but steadily decreased over
the course of the reaction. We hypothesized, therefore, that 5 might
be a decomposition product arising from over-reduction and re-
ductive cleavage of 4. Indeed, when 4 was isolated and resubjected
to the reaction conditions for 24 h, we observed formation of 5 in
33% yield, which suggested that the long reaction times were in
part responsible for the formation of 5. We therefore sought con-
ditions that would accelerate the overall rate of conversion and
limit the formation of this undesired side product.
1
2
3
4
5
6
7
8
A
A
A
A
A
A
A
A
Ar¼Ph
1 h
86
70
83d
76
77
77
84
5e
Ar¼4-CleC6H4
Ar¼4-CF3eC6H4
Ar¼4-AcOeC6H4
Ar¼2-naphthyl
Ar¼2-furyl
30 min
30 min
1 h
1.5 h
30 min
30 min
6 h
Ar¼2-FeC6H4
Ar¼2-MeeC6H4
In an initial screen of solvents, we found that the presence of
water had a profound influence on the rate of the reaction. Upon
addition of 10 equiv of water, the reaction time decreased dramati-
cally from 9.5 to 1 h (Table 1, entries 1 and 2). Importantly, very little
of the undesired over-reduction product 5 was formed, and the
hetero-DielseAlder cycloadduct could be isolated in 86% yield. Wa-
ter proved to be a uniquely effective protic additive;8 while both
methanol and trifluoroethanol also afforded an increase in the rate of
the reaction, neither provided good yields of the desired [4þ2]
cycloadduct. Control studies indicated that LiBF4 was an essential
additive. No consumption of the starting bis(enone) occurred when
LiBF4 was either omitted from the reaction or was replaced by
Bu4NþBFꢀ4 . This indicates that the Lewis acidity of the lithium cation
9
A
A
B
B
B
R¼CH2OBn
R¼Me
20 min
2 h
10 min
1.5 h
6 h
76
39
73
10
11
12
13
R¼Me
R¼i-Pr
58
R¼t-Bu
12e
14
B
5 h
17e
a
All reactions were irradiated with a 200 W tungsten filament light bulb at
a distance of 30 cm.
b
Method A: Bis(enone) substrate (1 equiv), Ru(bpy)3Cl2 (0.05 equiv), LiBF4
(2 equiv), i-Pr2NEt (3 equiv), and H2O (10 equiv) in degassed MeCN (0.1 M). Method
B: Bis(enone) substrate (1 equiv), Ru(bpy)3Cl2 (0.05 equiv), Mg(ClO4)2 (2 equiv), and
i-Pr2NEt (5 equiv) in degassed MeCN (0.025 M).
Table 1
Optimization of [4þ2] cycloaddition of 3a
c
Data represent the average isolated yields from two reproducible experiments,
unless otherwise noted.
d
Isolated yield of a single experiment.
e
Yield of a single experiment, determined by 1H NMR spectroscopy against an
internal standard.
We also became interested in exploring the cycloadditions of
unsymmetrical bis(enones) in which two possible constitutional
isomers could reasonably be formed. We examined the reactions of
a number of substrates bearing one aryl enone and one aliphatic
Entry
Additives
Time (h)
Yield % (4/5)b,c
1
2
3
4
5
6
LiBF4 (2 equiv)
9.5
1
1
1
1
28/41
86d/<5
25/19e
61/25
0/0
enone under our optimized reaction conditions. An
a-benzyloxy
LiBF4 (2 equiv), H2O (10 equiv)
LiBF4 (2 equiv), MeOH (10 equiv)
LiBF4 (2 equiv), CF3CH2OH (10 equiv)
H2O (10 equiv)
enone underwent efficient cycloaddition to afford
a
single
regioisomer of the hetero-DielseAlder product (entry 9). Other
substrates were less successful. A methyl enone required signifi-
cantly longer reaction times and consequently afforded lower
yields of the desired cycloadduct, although the regioselectivity of
this process was also excellent (entry 10). Upon careful optimiza-
tion, we were able to increase the efficiency of this reaction to 73%
by removing water and replacing the LiBF4 additive with Mg(ClO4)2
(entry 11). Other aliphatic enones also underwent cycloaddition
under these conditions, although the yields of these reactions
Bu4NþBF4
e
(2 equiv), H2O (10 equiv)
1
0/0
a
Reactions conducted in degassed MeCN (0.1 M) under irradiation with a 200 W
tungsten filament light bulb at a distance of 30 cm.
b
Yields determined by 1H NMR spectroscopy against an internal standard unless
otherwise noted.
c
The products were formed in >10:1 dr unless otherwise noted.
Isolated yield.
Compound 5 was formed as a 2:1 mixture of diastereomers in this experiment.
d
e

4444
A.E. Hurtley et al. / Tetrahedron 67 (2011) 4442e4448
decreased with increasing steric demand (entries 12e14). Reactions
involving enoates and -unsaturated thioesters were unsuccess-
a,b
ful under both sets of conditions.
The high level of regioselectivity observed in the cycloaddition
of unsymmetrical bis(enones) (e.g., 6) can be rationalized by the
mechanism outlined in Scheme 2, which is based upon Krische and
Bauld’s proposal that radical anion cycloadditions proceed in
a step-wise fashion.7 Photoexcitation of RuðbpyÞ23þ with visible
light affords an excited state that can undergo efficient reductive
quenching by i-Pr2NEt. The Lewis acid-activated enone complex
([LA]-6) can then accept an electron from the resulting RuðbpyÞ3þ
reductant to afford an activated radical anion intermediate (7) that
should undergo
b,b coupling to afford a monocyclized distonic
radical anion intermediate (8). Formation of the carboneoxygen
bond could proceed to form two possible isomeric ketyl radicals (9
and 10). We speculate that the greater stabilization of the aryl ketyl
radical may then serve as a driving force for selective formation of
9. Finally, the neutral hetero-DielseAlder cycloadduct is produced
upon loss of one electron, either to another equivalent of enone in
a chain propagation step or to the photogenerated amine radical
cation in a chain termination step.
Scheme 3. Diastereoselective functionalization of 4.
Scheme 2. Proposed mechanism for regioselective hetero-DielseAlder cycloaddition of unsymmetrical bis(enone) 6.
The dihydropyrans formed in this study can be synthetically
elaborated in a number of ways (Scheme 3). The enol ether func-
tionality of 4 can be converted to an acetal (12) upon treatment
with methanol and catalytic PTSA in excellent yield and diaster-
eoselectivity. Dihydroxylation of the olefin under Upjohn condi-
tions10 similarly provides the corresponding diol (13) with high
stereochemical purity. Finally, catalytic hydrogenation of 4 reduces
both the enol ether and the aryl ketone, introducing two new
stereocenters with very high diastereoselectivity in the doubly re-
duced product (14).
The origins of the chemoselectivity for [2þ2] versus [4þ2]
pathways in these radical anion processes are not clear at this time,
but the length of the aliphatic tether appears to be critical. Sub-
jecting the three-carbon tethered bis(enone) 1 to the optimized
conditions for 2 in Table 2 produced only [2þ2] cycloadduct and
none of the hetero-DielseAlder product. Five- and six-carbon
tethers that would afford medium-sized rings produced neither
cycloadduct. We speculate that the initial bond-forming event in
the stepwise cycloaddition of 1 has a kinetic preference for for-
mation of the cis cyclopentane isomer. Subsequent coupling of the
a,a carbons would afford the [3.2.0] bicycloheptane ring structure
observed in the intramolecular cyclobutanation.4a On the other
hand, we speculate that the initial carbon-carbon bond formation
in the cycloaddition of 3 produces a trans-substituted cyclohexane
intermediate. Coupling of the
a positions would afford a trans
[4.2.0] ring system that we would expect to be prohibitively
strained, while formation of a new CeO bond would produce a less
energetically unfavorable trans oxadecalin bicycle.
In summary, our group’s investigations of visible light photo-
catalysis have led to the discovery of an interesting intramolecular
hetero-DielseAlder cycloaddition. This reactivity is notable for
a number of reasons. First, the intermediacy of an enone radical
anion facilitates the efficient coupling of
a dienophile and
heterodiene that are both electron-deficient, which enables the

A.E. Hurtley et al. / Tetrahedron 67 (2011) 4442e4448
4445
construction of a cycloadduct that is difficult to access upon ther-
mal activation. Second, the diastereoselectivity of the process is
high, and the products are amenable to a variety of further syn-
thetic manipulations. Finally, one of the most intriguing unan-
swered questions is how the effect of the tether length controls the
chemoselectivity for [4þ2] versus [2þ2] cycloaddition. Studies to
elucidate the origins of this divergent reactivity are underway in
our laboratory, and these investigations provide a promising
framework for further studies of the chemistry of photogenerated
radical anions.
approximately 4 mL and purified immediately by silica gel flash
column chromatography.
3.2.3. (Table 2, entry 1). Experiment 1: conducted using method A
with 100 mg (0.314 mmol) bis(enone), 12 mg (0.016 mmol) Ru(b-
py)3Cl2$6H2O, 60 mg (0.64 mmol) LiBF4, 57
mL (3.1 mmol) H2O,
164 L (0.942 mmol) i-Pr2NEt, and 3.1 mL MeCN and an irradiation
m
time of 60 min. Purification by flash column chromatography (20:1
hexanes/EtOAc) afforded 85 mg cycloadduct (0.27 mmol, 85%). Ex-
periment 2: 100 mg (0.314 mmol) bis(enone), 12 mg (0.016 mmol)
Ru(bpy)3Cl2$6H2O, 59 mg (0.63 mmol) LiBF4, 57 mL (3.1 mmol) H2O,
164 mL (0.942 mmol) i-Pr2NEt, and 3.1 mL MeCN. Isolated 86 mg
3. Experimental section
3.1. General methods
cycloadduct (0.27 mmol, 86%) as a white solid (mp 60e64 ꢁC). IR
(thin film): 2928, 1684, 1447, 1270 cmꢀ1. 1H NMR: (500 MHz, CDCl3)
d
8.13 (ddd, J¼8.1,1.3,1.3 Hz, 2H), 7.59 (tt, J¼7.4,1.3 Hz,1H), 7.54 (ddd,
J¼7.8, 1.3, 1.3 Hz, 2H), 7.31e7.23 (m, 3H), 5.31 (d, J¼1.7 Hz, 1H), 4.93
(d, J¼10.4 Hz,1H), 2.17 (dddd, J¼10.5,10.5, 2.2, 2.2 Hz,1H),1.95e1.74
(m, 4H), 1.56 (dddd, J¼11.9, 2.2, 2.2, 2.2 Hz, 1H), 1.39 (qt, J¼12.8,
3.3 Hz,1H), 1.29 (qt, J¼12.8, 3.3 Hz, 1H), 1.21 (qd, J¼12.8, 3.3 Hz, 1H),
Acetonitrile, dichloromethane, and tetrahydrofuran were puri-
fied by elution through alumina as described by Grubbs.11 Diiso-
propylethylamine was purified by distillation from CaH2
immediately prior to use. Ru(bpy)3Cl2$6H2O was purchased from
Strem and used without purification. LiBF4 and Mg(ClO4)2 were
purchased from SigmaeAldrich and Strem, respectively, and stored
in a glove box under an atmosphere of nitrogen. Millipore water
was used in all photochemical reactions depicted in Table 2 and
prepared as a stock solution in acetonitrile. A 200 W (3980 lumens)
GE Crystal Clear tungsten filament light bulb was used for all
photochemical reactions and the solvent required for these re-
actions was degassed by three freeze-pump-thaw cycles. Di-
astereomer ratios for all products were determined by 1H NMR
analysis of the isolated products after flash column chromatogra-
phy. Flash column chromatography was performed with Silicycle
1.07 (qd, J¼12.6, 3.5 Hz, 1H); 13C NMR: (125 MHz, CDCl3)
d 196.9,
149.6, 135.7, 135.1, 133.5, 129.4, 128.6, 128.1, 128.0, 124.4, 102.5, 83.1,
41.3, 38.4, 32.7, 27.7, 26.0, 25.9. HRMS (EI) calculated for [C22H22O2]þ
m/z requires 318.1615, found 318.1599.
3.2.4. (Table 2, entry 2). Experiment 1: conducted using method A
with 99 mg (0.26 mmol) bis(enone), 10 mg (0.013 mmol) Ru(b-
py)3Cl2$6H2O, 49 mg (0.53 mmol) LiBF4, 46
mL (2.6 mmol) H2O,
135 L (0.774 mmol) i-Pr2NEt, and 2.6 mL MeCN and an irradiation
m
time of 30 min. Purification by flash column chromatography (20:1
hexanes/EtOAc) afforded 69 mg cycloadduct (0.18 mmol, 69%). Ex-
periment 2: 100 mg (0.258 mmol) bis(enone), 9.7 mg (0.013 mmol)
ꢀ
40e63 A silica (230e400 mesh). All glassware was oven-dried prior
Ru(bpy)3Cl2$6H2O, 48 mg (0.52 mmol) LiBF4, 46
135 L (0.774 mmol) i-Pr2NEt, and 2.6 mL MeCN. Isolated 71 mg
cycloadduct (0.18 mmol, 71%) as awhite solid (mp 42e46 ꢁC). IR (thin
film): 2922,1692,1491,1092 cmꢀ1. 1H NMR: (500 MHz, CDCl3)
8.05
mL (2.6 mmol) H2O,
to use. 1H and 13C NMR data for all previously uncharacterized
compounds were obtained using a Varian Unity-500 spectrometer
and are referenced to TMS (0.0 ppm) and CDCl3 (77.0 ppm), re-
spectively. Mass spectrometry was performed with a Waters
Micromass LCT (electrospray ionization, time-of-flight analyzer).
m
d
(dt, J¼8.7, 2.0 Hz, 2H), 7.44 (dt, J¼8.7, 2.0 Hz, 4H), 7.25 (dt, J¼8.7,
2.0 Hz, 2H), 5.30 (d, J¼1.8 Hz,1H), 4.86 (d, J¼10.5 Hz,1H), 2.15 (dddd,
J¼10.8, 10.8, 2.3, 2.3 Hz, 1H), 1.90 (dddd, J¼13.0, 2.5, 2.5, 2.5 Hz, 1H),
1.85e1.75 (m, 3H), 1.54 (dddd, J¼13.0, 2.5, 2.5, 2.5 Hz, 1H), 1.44e1.15
(m, 3H), 1.065 (dddd, J¼12.7, 12.7, 12.7, 3.8 Hz, 1H); 13C NMR:
3.2. Photocatalytic hetero-DielseAlder cycloadditions
3.2.1. General procedure: method A (Table 2). To an oven-dried
25 mL Schlenk tube equipped with a magnetic stir bar were added
bis(enone) (1 equiv), Ru(bpy)3Cl2$6H2O (0.05 equiv), LiBF4
(2 equiv), MeCN (0.1 M), H2O (10 equiv) as a stock solution in
MeCN, and i-Pr2NEt (3 equiv). The tube was sealed and degassed by
three freeze-pump-thaw cycles under nitrogen in the absence of
light. The reaction mixture was then stirred in a water bath at room
temperature and irradiated with a 200 W tungsten filament light
bulb at a distance of 30 cm. Upon consumption of the bis(enone),
the reaction mixture was passed across a short plug of silica with
a mixture of either hexanes/EtOAc or hexanes/Et2O, concentrated in
vacuo to approximately 4 mL and then purified immediately by
flash column chromatography on silica gel.
(125 MHz, CDCl3) d 195.5,148.5,140.1,133.8,133.4,130.8,129.0,128.3,
125.7, 103.0, 83.3, 41.2, 38.4, 32.6, 27.6, 26.0, 25.8. HRMS (EI) calcu-
lated for m/z [C22H20Cl2O2]þ requires 386.0835, found 386.0848.
3.2.5. (Table 2, entry 3). Conducted using method A with 81 mg
(0.18 mmol) bis(enone), 8 mg (0.01 mmol) Ru(bpy)3Cl2$6H2O,
37 mg (0.39 mmol) LiBF4, 32 mL (1.8 mmol) H2O, 92 mL (0.53 mmol)
i-Pr2NEt, and 1.8 mL MeCN and an irradiation time of 30 min. Pu-
rification by flash column chromatography (30:1 hexanes/EtOAc)
afforded 68 mg cycloadduct (0.15 mmol, 83%) as a white solid (mp
48e52 ꢁC). IR (thin film): 2932, 1696, 1326, 1169 cmꢀ1 1H NMR:
.
(500 MHz, CDCl3)
d
8.22 (d, J¼8.3 Hz, 2H), 7.75 (d, J¼8.3 Hz, 2H),
7.62 (d, J¼8.3 Hz, 2H), 7.54 (d, J¼8.3 Hz, 2H), 5.44 (d, J¼1.7 Hz, 1H),
4.93 (d, J¼10.4 Hz,1H), 2.20 (dddd, J¼10.4,10.4, 2.3, 2.3 Hz,1H),1.94
(dd, J¼12.5, 2.4 Hz, 1H), 1.87e1.77 (m, 3H), 1.56 (dq, J¼10.1, 2.7 Hz,
1H), 1.47e1.18 (m, 3H), 1.10 (qd, J¼12.4, 3.7 Hz, 1H); 13C NMR:
3.2.2. General procedure: method B (Table 2). To an oven-dried
50 mL Schlenk tube equipped with a magnetic stir bar were added
Ru(bpy)3Cl2$6H2O (0.05 equiv), Mg(ClO4)2 (2 equiv), and MeCN
(0.025 M). The mixture was stirred until homogenous and then
charged with the bis(enone) (1 equiv) and i-Pr2NEt (3 equiv). The
tube was sealed and degassed by three freeze-pump-thaw cycles
under nitrogen in the absence of light. The reaction mixture was
then stirred in a water bath at room temperature and irradiated
with a 200 W tungsten filament light bulb at a distance of 30 cm.
Upon consumption of the bis(enone), the reaction mixture was
passed across a 6 inch plug of silica with a mixture of hexanes/Et2O.
The reaction mixture was then concentrated in vacuo to
(125 MHz, CDCl3)
d
198.4, 151.0, 140.9, 140.8, 137.4 (q, J¼33.0 Hz),
132.6 (q, J¼33.0), 132.3, 130.0, 129.5, 128.4 (q, J¼3.6 Hz), 127.9 (q,
J¼3.6 Hz), 127.2, 125.7, 125.1, 123.5, 122.9, 107.5, 86.1, 43.7, 40.8, 35.1,
30.2, 28.6, 28.4. HRMS (EI) calculated for m/z [C24H20F6O2]þ re-
quires 454.1362, found 454.1352.
3.2.6. (Table 2, entry 4). Experiment 1: conducted using method A
with 101 mg (0.232 mmol) bis(enone), 9 mg (0.01 mmol) Ru(b-
py)3Cl2$6H2O, 42 mg (0.45 mmol) LiBF4, 41
mL (2.3 mmol) H2O,
120 L (0.690 mmol) i-Pr2NEt, and 2.3 mL MeCN and an irradiation
m

4446
A.E. Hurtley et al. / Tetrahedron 67 (2011) 4442e4448
time of 30 min. Purification by flash column chromatography (5:1
hexanes/acetone) afforded 77 mg cycloadduct (0.18 mmol, 76%).
Experiment 2: 92.0 mg (0.212 mmol) bis(enone), 8 mg (0.01 mmol)
time of 30 min. Purification by flash column chromatography (20:1
hexanes/Et2O) afforded 84 mg cycloadduct (0.24 mmol, 84%). Ex-
periment 2: 99.8 mg (0.282 mmol) bis(enone), 11 mg (0.015 mmol)
Ru(bpy)3Cl2$6H2O, 41 mg (0.44 mmol) LiBF4, 39
mL (2.2 mmol) H2O,
Ru(bpy)3Cl2$6H2O, 52 mg (0.55 mmol) LiBF4, 51 mL (2.8 mmol) H2O,
114
m
L (0.651 mmol) i-Pr2NEt, and 2.2 mL MeCN. Isolated 70 mg
148 mL (0.847 mmol) i-Pr2NEt, and 2.8 mL MeCN. Isolated 84 mg
cycloadduct (0.16 mmol, 76%) as a white solid (mp 42e46 ꢁC). IR
cycloadduct (0.24 mmol, 84%) as a white solid (mp 34e36 ꢁC). IR
(thin film): 2929, 1758, 1685, 1599, 1506, 1370, 1198 cmꢀ1. 1H NMR:
(thin film): 2928, 1693, 1610, 1490, 1451, 1267, 1211 cmꢀ1. 1H NMR:
(500 MHz, CDCl3)
d
8.17 (dt, J¼8.8, 1.9 Hz, 2H), 7.54 (dt, J¼8.8, 1.9 Hz,
(500 MHz, CDCl3)
d
7.86 (td, J¼7.6, 1.7 Hz, 1H), 7.54 (m, 1H), 7.45 (td,
2H), 7.20 (dt, J¼8.8, 1.9 Hz, 2H), 7.01 (dt, J¼8.8, 1.9 Hz, 2H), 5.28 (d,
J¼1.9 Hz, 1H), 4.86 (d, J¼10.4 Hz, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 2.15
(dddd, J¼10.6, 10.6, 2.5, 2.5 Hz, 1H), 1.90 (dddd, J¼12.7, 2.3, 2.3,
2.3 Hz, 1H), 1.86e1.75 (m, 3H), 1.54 (dddd, J¼12.7, 2.3, 2.3, 2.3 Hz,
1H), 1.45e1.15 (m, 3H), 1.07 (qd, J¼12.7, 3.9 Hz, 1H); 13C NMR:
J¼7.9, 1.7 Hz, 1H), 7.25 (td, J¼7.8, 1.1 Hz, 1H), 7.21e7.12 (m, 2H),
7.04e6.98 (m, 2H), 5.39 (bs, 1H), 5.01 (d, J¼10.4 Hz, 1H), 2.19 (dddd,
J¼11.0, 11.0, 2.3, 2.3 Hz, 1H), 1.91e1.75 (m, 4H), 1.70 (dddd, J¼12.6,
2.7, 2.0, 2.0 Hz, 1H), 1.45e1.08 (m, 4H); 13C NMR: (125 MHz, CDCl3)
d
196.9 (d, J¼3.2 Hz), 161.4 (d, J¼254.0 Hz), 159.8 (d, J¼251.2 Hz),
(125 MHz, CDCl3)
d
195.5, 169.4, 168.8, 154.6, 150.5, 148.8, 133.1,
144.7 (d, J¼3.5 Hz), 134.6 (d, J¼9.8 Hz), 130.9 (d, J¼2.3 Hz), 128.9 (d,
J¼8.6 Hz), 128.1 (d, J¼2.2 Hz), 125.8 (d, J¼13.1 Hz), 124.5
(d, J¼3.2 Hz), 123.8 (d, J¼3.6 Hz), 123.3 (d, J¼10.8 Hz), 116.7 (d,
J¼23.2 Hz), 115.8 (d, J¼23.2 Hz), 107.9 (d, J¼12.1 Hz), 83.4 (d,
J¼5.0 Hz), 40.9, 38.5, 27.4, 26.1, 25.9, 32.6. HRMS (EI) calculated for
[C22H20F2O2]þ m/z requires 354.1426, found 354.1423.
132.8, 131.2, 125.6, 121.8, 121.3, 102.7, 83.6, 41.2, 38.4, 32.6, 27.6,
26.0, 25.8, 21.1, 21.1. HRMS (EI) calculated for [C26H26O6]þ requires
m/z 434.1724, found 434.1714.
3.2.7. (Table 2, entry 5). Experiment 1: conducted using method A
with 101 mg (0.240 mmol) bis(enone), 9 mg (0.01 mmol) Ru(b-
py)3Cl2$6H2O, 44 mg (0.47 mmol) LiBF4, 43
mL (2.4 mmol) H2O,
3.2.10. (Table 2, entry 9). Experiment 1: conducted using method A
125 L (0.717 mmol) i-Pr2NEt, and 2.4 mL MeCN and an irradiation
m
with 100 mg (0.275 mmol) bis(enone), 11 mg (0.014 mmol) Ru(b-
time of 1.5 h. Purification by flash column chromatography (20:1
hexanes/Et2O) afforded 75 mg cycloadduct (0.18 mmol, 75%). Ex-
periment 2: 100 mg (0.238 mmol) bis(enone), 9 mg (0.01 mmol)
py)3Cl2$6H2O, 52 mg (0.56 mmol) LiBF4, 50
mL (2.8 mmol) H2O,
144 L (0.828 mmol) i-Pr2NEt, and 2.8 mL MeCN and an irradiation
m
time of 20 min. Purification by flash column chromatography (10:1
hexanes/Et2O) afforded 75 mg cycloadduct (0.21 mmol, 75%). Ex-
periment 2: 100 mg (0.276 mmol) bis(enone), 10 mg (0.014 mmol)
Ru(bpy)3Cl2$6H2O, 45 mg (0.48 mmol) LiBF4, 43
125 L (0.717 mmol) i-Pr2NEt, and 2.4 mL MeCN. Isolated 79 mg
cycloadduct (0.19 mmol, 79%) as a colorless oil. IR (thin film): 2928,
1683, 1279, 1123 cmꢀ1 1H NMR: (500 MHz, CDCl3)
8.75 (s, 1H),
mL (2.4 mmol) H2O,
m
Ru(bpy)3Cl2$6H2O, 52 mg (0.56 mmol) LiBF4, 50
144 L (0.828 mmol) i-Pr2NEt, and 2.8 mL MeCN. Isolated 76 mg
cycloadduct (0.21 mmol, 76%) as a colorless oil. IR (thin film): 2927,
1677, 1448, 1072 cmꢀ1. 1H NMR: (500 MHz, CDCl3)
mL (2.8 mmol) H2O,
.
d
m
8.19 (dd, J¼8.8,1.7 Hz,1H), 8.03 (s,1H), 7.93 (t, J¼7.9 Hz, 2H), 7.89 (d,
J¼8.1 Hz, 1H), 7.80e7.67 (m 4H), 7.61 (td, J¼7.9, 0.9 Hz, 1H), 7.52
(td, J¼7.9, 0.9 Hz, 1H), 7.43e7.37 (m, 2H), 5.49 (d, J¼1.7 Hz, 1H), 5.16
(d, J¼10.4 Hz, 1H), 2.27 (dddd, J¼10.4, 10.4, 1.5, 1.5 Hz, 1H), 1.96 (qd,
J¼10.5, 3.1 Hz, 2H), 1.82 (dt, J¼12.4, 2.4 Hz, 1H), 1.77 (dt, J¼12.4,
2.4 Hz, 1H), 1.61 (dd, J¼12.2, 2.4 Hz, 1H), 1.49e1.22 (m, 3H), 1.12 (qd,
d
8.07 (dt, J¼7.5,
1.2 Hz, 2H), 7.57 (tt, J¼7.5, 1.2 Hz, 1H), 7.43 (td, J¼7.5, 1.2 Hz, 2H),
7.36e7.25 (m, 5H), 4.84 (d, J¼10.4 Hz, 1H), 4.80 (s, 1H), 4.57 (s, 2H),
3.96 (ABq, J¼12.0 Hz, 2H), 2.03 (dddd, J¼11.0, 11.0, 1.4, 1.4 Hz, 1H),
1.84e1.69 (m, 4H), 1.49 (ddd, J¼12.8, 2.3, 2.3 Hz, 1H), 1.39e1.19 (m,
2H), 1.12 (dddd, J¼12.8, 12.8, 12.8, 3.2 Hz, 1H), 1.00 (dddd, J¼12.8,
J¼13.0, 3.7 Hz, 1H); 13C NMR: (125 MHz, CDCl3)
d 196.9, 149.7, 135.8,
133.2, 133.2, 133.1, 132.5, 132.4, 131.5, 129.9, 128.8, 128.5, 128.4,
127.8, 127.7, 127.5, 126.8, 126.1, 125.9, 124.8, 123.4, 122.6, 103.4, 83.1,
41.6, 38.7, 32.7, 27.8, 26.1, 25.9. HRMS (EI) calculated for [C30H26O2]þ
requires m/z 418.1928, found 418.1936.
12.8, 12.8, 3.7 Hz, 1H); 13C NMR: (125 MHz, CDCl3)
d 197.0, 149.0,
138.2, 135.8, 133.4, 129.3, 128.5, 128.3, 127.8, 127.6, 104.9, 82.6, 72.3,
69.9, 41.4, 37.8, 32.4, 27.7, 26.0, 25.9. HRMS (EI) calculated for
[C24H26O3]þ requires m/z 362.1877, found 362.1869.
3.2.8. (Table 2, entry 6). Experiment 1: conducted using method A
3.2.11. (Table 2, entry 11). Experiment 1: conducted using method
with 102 mg (0.342 mmol) bis(enone), 13 mg (0.018 mmol) Ru(b-
B with 101 mg (0.394 mmol) bis(enone), 14 mg (0.019 mmol)
py)3Cl2$6H2O, 62 mg (0.66 mmol) LiBF4, 60
mL (3.4 mmol) H2O,
Ru(bpy)3Cl2$6H2O, 174 mg (0.779 mmol) Mg(ClO4)2, 340 mL
175 L (1.01 mmol) i-Pr2NEt, and 3.4 mL MeCN and an irradiation
m
(1.95 mmol) i-Pr2NEt, and 15.6 mL MeCN and an irradiation time of
10 min. Purification by flash column chromatography (20:1 hex-
anes/EtOAc) afforded 75 mg cycloadduct (0.29 mmol, 74%). Exper-
iment 2: 100 mg (0.386 mmol) bis(enone), 14 mg (0.019 mmol)
time of 30 min. Purification by flash column chromatography (15:1
hexanes/EtOAc) afforded 79 mg cycloadduct (0.26 mmol, 77%). Ex-
periment 2: 102 mg (0.340 mmol) bis(enone), 13 mg (0.017 mmol)
Ru(bpy)3Cl2$6H2O, 62 mg (0.67 mmol) LiBF4, 60
175 L (1.01 mmol) i-Pr2NEt, and 3.4 mL MeCN. Isolated 77 mg
cycloadduct (0.26 mmol, 76%) as a colorless oil. IR (thin film): 2930,
1668,1464 cmꢀ1.1H NMR: (500 MHz, CDCl3)
m
L (3.4 mmol) H2O,
Ru(bpy)3Cl2$6H2O, 173 mg (0.775 mmol) Mg(ClO4)2, 340 mL
(1.95 mmol) i-Pr2NEt, and 15.6 mL MeCN. Isolated 72 mg cyclo-
adduct (0.28 mmol, 72%) as a colorless oil. IR (thin film): 2923,1680,
m
d
7.67 (dd, J¼1.6, 0.6 Hz,
1448,1280 cmꢀ1. 1H NMR: (500 MHz, CDCl3)
d
8.05 (dt, J¼7.7,1.3 Hz,
1H), 7.40 (dd, J¼3.7, 0.6 Hz, 1H), 7.36 (dd, J¼1.4, 1.4 Hz, 1H), 6.55 (dd,
J¼3.7, 1.6 Hz, 1H), 6.39e6.36 (m, 2H), 5.29 (d, J¼1.8 Hz, 1H), 4.86
(d, J¼10.6 Hz, 1H), 2.14 (dddd, J¼10.6, 10.6, 2.2, 2.2 Hz, 1H), 1.90
(dddd, J¼13.0, 1.3,1.3,1.3 Hz,1H),1.79 (dddd, J¼12.4, 2.2, 2.2, 2.2 Hz,
1H), 1.69 (dddd, J¼10.5, 10.5, 10.5, 3.0 Hz, 1H), 1.60e1.53 (m, 1H),
2H), 7.58 (tt, J¼7.7, 1.3 Hz, 1H), 7.47 (tt, J¼7.7, 1.3 Hz, 2H), 4.82 (d,
J¼10.3 Hz, 1H), 4.43 (s, 1H), 1.95 (dddd, J¼11.3, 11.3, 1.8, 1.8 Hz, 1H),
1.79 (dd, J¼2.0, 0.8 Hz, 3H), 1.77e1.64 (m, 4H), 1.44 (dddd, J¼12.4,
2.7, 2.7, 2.7 Hz, 1H), 1.37e1.18 (m, 2H), 1.07 (dddd, J¼12.4, 12.4, 12.4,
2.7 Hz, 1H), 0.97 (dddd, J¼12.6, 12.6, 12.6, 3.6 Hz, 1H); 13C NMR:
1.44e1.08 (m, 4H); 13C NMR: (125 MHz, CDCl3)
d
185.6, 150.8, 149.5,
(125 MHz, CDCl3) d 197.5, 149.2, 136.0, 133.4, 129.2, 128.5, 128.5,
147.4, 142.7, 142.0, 120.4, 112.3, 111.1, 105.9, 101.7, 83.3, 42.1, 38.0,
32.5, 27.2, 25.9, 25.8. HRMS (EI) calculated for m/z [C18H18O4]þ re-
quires 298.1200, found 298.1187.
101.5, 82.3, 41.7, 38.1, 32.7, 27.7, 25.9, 25.9,19.7. HRMS (EI) calculated
for [C17H20O2]þ requires m/z 256.1458, found 256.1455.
3.2.12. (Table 2, entry 12). Experiment 1: conducted using method
3.2.9. (Table 2, entry 7). Experiment 1: conducted using method A
B with 100 mg (0.353 mmol) bis(enone), 14 mg (0.018 mmol)
with 99.7 mg (0.281 mmol) bis(enone), 11 mg (0.014 mmol) Ru(b-
Ru(bpy)3Cl2$6H2O, 159 mg (0.710 mmol) Mg(ClO4)2, 307 mL
py)3Cl2$6H2O, 52 mg (0.56 mmol) LiBF4, 51
m
L (2.8 mmol) H2O,
(1.76 mmol) i-Pr2NEt, and 14.1 mL MeCN and an irradiation time of
1.5 h. Purification by flash column chromatography (20:1 hexanes/
148 L (0.847 mmol) i-Pr2NEt, and 2.8 mL MeCN and an irradiation
m

A.E. Hurtley et al. / Tetrahedron 67 (2011) 4442e4448
4447
Et2O) afforded 58 mg cycloadduct (0.20 mmol, 58%). Experiment 2:
101 mg (0.354 mmol) bis(enone), 14 mg (0.018 mmol) Ru(b-
py)3Cl2$6H2O, 158 mg (0.708 mmol) Mg(ClO4)2, 307 mL (1.76 mmol)
flask was fitted with a regulator and filled with H2 and evacuated
twice, then filled with 20 psi of H2. The reaction was allowed to stir
at room temperature for 3 h, and then the excess H2 was vented.
The reaction was filtered through Celite and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (8:1 hexanes/EtOAc) to afford the product (70 mg, 0.22 mmol,
69%) as a clear oil. IR (thin film): 3553, 3432, 2926, 2852 cmꢀ1. 1H
i-Pr2NEt, and 14.1 mL MeCN. Isolated 58 mg cycloadduct
(0.20 mmol, 58%) as a colorless oil. IR (thin film): 2927, 1674, 1448,
1268 cmꢀ1. 1H NMR: (500 MHz, CDCl3)
d
8.07 (ddd, J¼7.8, 1.2, 1.0 Hz,
2H), 7.57 (tt, J¼7.8, 1.2 Hz, 1H), 7.46 (ddd, J¼7.8, 7.8, 1.0 Hz, 2H), 4.70
(d, J¼10.4 Hz, 1H), 4.42 (s, 1H), 2.27 (sept, J¼6.8 Hz, 1H), 1.95 (dddd,
J¼10.5, 10.5, 1.8, 1.8 Hz, 1H), 1.80e1.59 (m, 4H), 1.47 (dddd, J¼13.0,
3.0, 3.0, 3.0 Hz, 1H), 1.38e1.16 (m, 2H), 1.24e0.92 (m, 8H); 13C NMR:
NMR: (500 MHz, CDCl3)
d
7.46 (dt, J¼7.0, 1.5 Hz, 2H), 7.39e7.26 (m,
8H), 4.80 (dd, J¼9.4, 3.2 Hz, 1H), 4.49 (dd, J¼11.3, 2.2 Hz, 1H), 3.70
(dd, J¼10.1, 3.3 Hz, 1H), 3.40 (d, J¼9.6 Hz, 1H, (OH)), 1.80 (dddd,
J¼12.4, 2.8, 2.8, 2.8 Hz, 1H), 1.73 (m, 1H), 1.67 (tt, J¼12.4, 2.8 Hz, 2H),
1.56 (dddd, J¼12.9, 2.8, 2.8, 2.8 Hz, 1H), 1.40 (tt, J¼11.7, 3.3 Hz, 1H),
1.27 (qt, J¼13.0, 3.7 Hz, 1H), 1.16 (q, J¼12.3 Hz, 1H), 1.12 (qt, J¼13.0,
3.7 Hz, 1H), 1.00 (qd, J¼12.1, 3.3 Hz, 1H), 0.89 (qd, J¼12.8, 3.7 Hz,
1H), 0.76 (qd, J¼10.2, 3.2 Hz, 1H); 13C NMR: (125 MHz, CDCl3)
(125 MHz, CDCl3) d 197.5, 157.6, 135.7, 133.3, 129.4, 128.4, 98.4, 83.2,
41.7, 37.9, 32.9, 32.0, 27.6, 26.0, 26.0, 20.5. HRMS (EI) calculated for
[C19H24O2]þ requires m/z 284.1771, found 284.1780.
3.3. Diastereoselective functionalization of cycloadduct 4
d
143.2, 140.6, 128.3, 128.0, 127.9, 127.5, 127.3, 125.8, 84.5, 80.1, 73.8,
3.3.1. (Compound 12, Scheme 3). To an oven-dried 10 mL round
bottom flask equipped with a magnetic stir bar were added
42.4, 41.7, 41.1, 32.7, 27.2, 25.9, 25.6. HRMS (EI) calculated for
[C22H26O2þNa]þ requires m/z 345.1825, found 345.1835.
cycloadduct
4
(100 mg, 0.314 mmol), p-TsOH$H2O (6 mg,
0.03 mmol), and methanol (3.2 mL). The reaction was allowed to
stir at room temperature for 3.5 h and then concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (8:1 hexanes/EtOAc) to afford the product (104 mg, 0.297 mmol,
95%) as a white solid (mp 91e97 ꢁC). IR (thin film): 3059, 2924,
3.4. Stereochemical determinations
NOE correlations were used to verify the relative stereochem-
istry of acetal 12 and dihydroxylation product 13, as well as the
regiochemistry of the cycloadduct in Table 2, entry 11. The structure
of 14 was determined unambiguously by single-crystal X-ray dif-
fraction of the corresponding p-nitrobenzoate ester.12 The struc-
tures of other compounds were assigned by analogy.
2854, 1679 cmꢀ1. 1H NMR: (500 MHz, CDCl3)
d
8.21 (ddd, J¼7.5, 1.0,
1.0 Hz, 2H), 7.61 (tt, J¼7.5, 1.0 Hz, 1H), 7.51 (t, J¼7.8 Hz, 2H), 7.49 (d,
J¼7.3 Hz, 2H), 7.34 (td, J¼7.4, 1.0 Hz, 2H), 7.28 (tt, J¼7.3, 1.0 Hz, 1H),
4.73 (d, J¼10.6 Hz, 1H), 3.05 (s, 3H), 2.09 (dd, J¼13.6, 3.6 Hz, 1H),
1.94 (qt, J¼11.8, 3.5 Hz, 1H), 1.70 (m, 4H), 1.51 (t, J¼13.0 Hz, 1H), 1.44
(dt, J¼12.8, 2.2 Hz, 1H), 1.35 (qt, J¼12.7, 3.5 Hz, 1H), 1.23 (qt, J¼12.8,
3.5 Hz, 1H), 1.07 (qd, J¼12.2, 3.5 Hz, 1H), 1.00 (qd, J¼12.2, 3.5 Hz,
Acknowledgements
We thank Dr. Ilia Guzei for performing the crystallographic de-
termination of the structure of 14. We are indebted to the ACS PRF
(49817-ND1), NIH (GM095666), Sloan Foundation, Beckman
Foundation, and Research Corporation for research funding. The
NMR facilities at UWeMadison are funded by the NSF (CHE-
9208463, CHE-9629688) and NIH (RR08389-01)
1H); 13C NMR: (125 MHz, CDCl3)
d 197.8, 142.0, 136.2, 133.3, 129.4,
128.5, 128.2, 127.8, 125.9, 100.8, 78.5, 49.5, 44.8, 43.2, 36.0, 32.8,
27.4, 25.9, 25.7. HRMS (EI) calculated for [C23H26O3ꢀMeO]þ re-
quires m/z 319.1693, found 319.1689.
3.3.2. (13, Scheme 3). A 1.5 dram vial was charged with potassium
osmate (VI) dihydrate (2 mg, 0.005 mmol) and sealed with a Teflon
cap. To the vial was added cycloadduct 4 (100 mg, 0.314 mmol), N-
methylmorpholine N-oxide (54 mg, 0.46 mmol), citric acid (60 mg,
0.31 mmol), and a magnetic stir bar, followed by tert-butanol
(0.93 mL) and distilled water (0.31 mL). The reaction was then
resealed and allowed to stir at room temperature for 23 h. Sodium
sulfite (40 mg, 0.32 mmol) was then added and the reaction was
stirred another 30 min. The reaction was diluted with water and
extracted twice with EtOAc. The combined organic extracts were
dried over sodium sulfate, filtered, and concentrated in vacuo to
a white solid. The solid was purified by flash column chromatog-
raphy on silica gel (10:1 toluene/acetone) then recrystallized in
hexanes and ethyl acetate to afford the product (65 mg, 0.18 mmol,
60%) as a white crystalline solid (mp 153e154 ꢁC). IR (thin film):
References and notes
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3447, 2931, 2856, 1684 cmꢀ1. 1H NMR: (500 MHz, acetone-d6)
d 8.14
(dt, J¼8.5, 1.5 Hz, 2H), 7.61 (dd, J¼8.5, 1.5 Hz, 1H), 7.60 (qt, J¼6.7,
1.3 Hz, 2H), 7.48 (tt, J¼7.8, 1.5 Hz, 2H), 7.29e7.21 (m, 3H), 5.63 (s, 1H
(OH)), 5.13 (d, J¼10.4 Hz, 1H), 3.40 (d, J¼9.3 Hz, 1H (OH)), 3.29 (t,
J¼9.3 Hz, 1H), 2.24 (m, 1H), 1.98 (qd, J¼11.0, 3.2 Hz, 1H), 1.86 (qd,
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(m, 2H),1.13e0.94 (m, 2H); 13C NMR: (125 MHz, acetone-d6)
d 196.1,
143.8, 136.4, 133.1, 129.2, 128.5, 127.5, 127.2, 126.6, 98.7, 76.7, 74.8,
42.7, 41.7, 28.4, 27.2, 25.7, 25.2. HRMS (EI) calculated for
[C22H24O4þNa]þ requires m/z 375.1567, found 375.1583.
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12. CCDC 807947 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.